Bemaciclib (also known as Abemaciclib or LY2835219), is a drug developed by Eli Lilly Company, and it is used for treatment of breast cancer taking the mechanism of suppressing the CKD 4/6. Phase I clinical data shows that, the mono-therapy of metastatic breast cancer patients with this drug is of relative good curative effect in early period, especially for those hormone-receptor positive breast cancer patients, the clinical benefit rate may be up to 61%, which means that the disease of the patients has been controlled for more than 24 weeks, or the tumor size has been reduced by more than 30%. At present, this drug has entered breast cancer Phase III clinical treatment, and clinical research of non-small cell lung cancer has started as well. As this drug still has no standard translated name in Chinese, the applicant hereby transliterates it to “”.
The chemical name of Bemaciclib is: N-[5-[(4-ethyl-1-piperazine)methyl]-2-pyridyl]-5-fluoro-4-[4-fluoro-2-methyl-1-isopropyl-1H-benzimidazole-6-yl]-2-pyrilamine (I), and its structural formula is:

Preparation of Bemaciclib has already been made research reports, and the reported synthetic route of PCT patent WO2010075074 originally developed by Eli Lilly Company is:

As for intermediate A and intermediate B, under actions of transition metal catalyst tri(dibenzylidene) di-palladium, ligand 4,5-bis (diphenylphosphino)-9,9-dimethyl and its cesium carbonate and others, the “pyridine amidogen” passing through intermediate A and the “pyrimidine halogen” in intermediate B go through substitution reaction, thus obtaining the target product: Bemaciclib.
This patent also reported preparation methods for intermediate A and B. Including, by virtue of condensation and reduction reaction between ethylpiperazine and 2-bromine-4-pyridylaldehyde under reducing agent, the “halogen bromine” in intermediate 1-(2-bromine-4-picolyl)-4-ethylpiperazine obtained and the “ammonia” go through ammonolysis reaction again under actions of metallic copper catalyst, thus intermediate A: 5-[(4-ethyl-piperazine-1-yl)methyl]-2-aminopyridine is finally well prepared.

In terms of intermediate B: 2,6-difluoro-4-bromaniline and N-isopropylacetamide go through amidine reaction under actions of chlorinating agent phosphorus oxychloride and acid-binging agent, and generate N-(2,6-difluoro-4-bromine-phenyl)-N′-isopropyl-ethanamidine, and such intermediate goes through cyclization reaction under potassium tert-butoxide, and generates 6-bromine-4-fluorine-1-isopropyl-2-methyl-1H-benzimidazole, and derivatives of such benzimidazole and the bis(pinacolato)diboron form borate ester compounds of derivatives of such benzimidazole under actions of palladium acetate and tricyclohexyl-phosphine, etc. And then such borate ester compounds and the 2,4-dichloro-4-fluoropyrimidine go through Suzuki reaction under actions of palladium catalyst, thus obtaining the intermediate B: 6-(2-chlorine-5-fluoro-pyrimidine-4-yl)-4-fluorine-1-isopropyl-2-methyl-1H-benzimidazole.

Analyzing the above-mentioned synthetic route, the synthetic thought applied is the method of gradual increment of functional groups, especially that during preparation of intermediate B and its target products, precious metal palladium catalyst and other special ligands are applied in many places, which makes the preparation cost hard to control. Meanwhile, during preparation process of intermediate B and its target products, there has been the circumstance of “several active functional groups compete for the same reaction” in many places, for example, the two chlorine atoms and the one fluorine atom on pyrimidine ring when making Suzuki reaction, and the one chlorine atom and the two fluorine atoms in intermediate B when intermediate A and B make condensation coupling, will all generate potential side reaction due to low selectivity, thus influencing both the quality and yield of the products. Therefore, with respect to the defects of the current processes, developing a simple and direct, economic and environment-friendly Bemaciclib technology with high quality, particularly seeking a process technology that is adaptable to the industrialized production, is of great realistic significance to the improvement of the drug's economic and social benefits.